3.2 HIV infection
Only 1 patient was infected with type 2 HIV (1 ITP), the other patients were infected with type 1 HIV. One patient was coinfected with HBV. Two patients had a positive HCV serology, 1 was cured and 1 had chronic hepatitis with HCV viremia. These 3 patients developed sarcoidosis (cutaneous form).
CDC stage at HIV infection was A for 24 patients, B for 7 patients, C for 3 patients (no data for 1 patient). Opportunistic diseases declared for these last patients were 1 pneumocystosis, 1 HIV encephalitis, and 1 Kaposi sarcoma.
Sixteen patients received antiretroviral therapy at HIV diagnosis and 18 had a deferred therapy (no data for 1 patient). Median viral load at HIV diagnosis was 87,600 copies/mL (IQR 100–6,500,000). Median CD4 T lymphocyte count, percentage, and CD4/CD8 T lymphocytes ratio at HIV diagnosis were 298.5/mm3 (IQR 17–1042), 19% (IQR 5–47%), 0.405 (IQR 0.23–1.31), respectively. Median viral load at HAART introduction was 32,800 copies/mL (IQR 100–6,500,000). Median CD4 T lymphocyte count, percentage, and CD4/CD8 T lymphocytes ratio at HAART introduction were 316/mm3 (IQR 4–714), 19% (IQR 1–32%), 0.38 (IQR 0.01–0.71), respectively.
3.3 Analysis of the chronology of AD occurrence in HIV-infected patients
Thirty patients were HIV-infected before the AD. Median time between HIV infection and AD was 113.5 months (IQR 0–306).
Fifteen patients were HIV-infected and HAART treated when they developed an AD. Median time between HAART introduction and AD was 88 months (IQR 0–195) for these patients. Five patients were HIV-infected and treated by biantiretroviral therapy. Ten patients were HIV-infected but without any antiretroviral treatment.
In 2 patients, the AD preceded HIV infection diagnosis (1 SLE and 1 sarcoidosis). For 3 patients, HIV infection was diagnosed concomitantly with the AD (less than 1 year between the diagnosis of the 2 disorders) (3 GBS).
For the 15 patients developing ITP, median viral load at ITP diagnosis was 8750 copies/mL (IQR 85–282,723). Median CD4 T lymphocyte count, percentage and CD4/CD8 T lymphocytes ratio at ITP diagnosis were 279.5/mm3 (IQR 53–975), 22% (IQR 4–48%), 0.4 (0.05–0.61).
For the other 15 patients who were HIV infected before the AD, median viral load at AD diagnosis was undetectable (<50 copies/mL) (IQR 0–6392). Median CD4 T lymphocyte count, percentage and CD4/CD8 T lymphocytes ratio at AD diagnosis were 475/mm3 (IQR 109–794), 30% (IQR 16–39%), 0.89 (IQR 0.29–1.32), respectively.
For the 3 patients with concomitant AD and HIV infection (3 GBS), median viral load, median CD4 T lymphocyte count, percentage, and CD4/CD8 T lymphocytes ratio at AD diagnosis were 680 copies/mL (IQR 0–90,000), 504/mm3 (IQR 485–714), 17% (only 1 data), 0.29 (only 1 data).
3.4 Treatments used in the management of the ADs
Regarding ADs except ITP, 2 of them were treated with steroids alone (1 sarcoidosis, 1 AHA). Two patients received steroids and hydroxychloroquine (1 SLE, 1 RA) and 7 patients were treated with intravenous immunoglobulins (2 GBS, 2 MG, 3 IM). One patient received salazopyrine, then methotrexate (RA); 1 patient was treated with several immunosuppressant drugs (methotrexate, azathioprine, rituximab) for refractory IM, which was an antisynthetase syndrome (anti-JO1 antibodies positive). In 7 patients the AD was controlled by using solely nonimmunosuppressant drugs and HAART.
Regarding ITP, 6 patients benefited from HAART introduction to control the disease, whereas the others (9/15) received intravenous immunoglobulins, and sometimes platelet transfusions or other immunosuppressant drugs (dapsone, steroids, and splenectomy).
These treatments were relatively well tolerated since no patient developed opportunistic infection or cancer during the follow-up. Six drug-induced cytopenias and 1 severe osteoporosis were reported (Table 3).
3.5 Evolution of the ADs and of the HIV infection at last follow-up
The median follow-up duration starting from the diagnosis of AD was 78 months (IQR 1–305).
For ITP, at last follow-up, median viral load was undetectable (<50 copies) (IQR 0–96,928). All of them, except one were HAART treated. Median CD4 T lymphocyte count, percentage and CD4/CD8 T lymphocytes ratio were 577/mm3 (IQR 94–1700), 30.2% (IQR 7.2–62%), 0.81 (IQR 0.07–2.84), respectively.
For the other ADs, at last follow-up, median viral load was undetectable (IQR 0–1056). All of them were HAART treated. Median CD4 T lymphocyte count, percentage and CD4/CD8 T lymphocytes ratio were 752/mm3 (IQR 262–1270), 35% (IQR 19–48%), 1 (IQR 0.36–1.59), respectively.
At last follow-up, all the ITP were in complete remission except one, which was in partial remission, with an uncontrolled HIV infection. For the other ADs, 11 were in complete remission, 8 were in partial remission, and 2 were refractory to the treatment (Table 3).
4.1 General features
The present retrospective study in a large database of HIV-infected patients allowed us to determine the characteristics of ADs, to make a cross sectional estimate of prevalence and to define their prognosis over a long median follow-up of 5 years. Moreover, we provided a comprehensive review of the clinical features, pathogenesis, and treatments of these ADs reported in the literature.
Women were not overrepresented in our study, which is unexpected regarding general HIV-negative population, but which is concordant with the literature in HIV-infected patients.[7,8] By focusing on the frequency of specific disorders, we found a proportion of sarcoidosis, GB, and IM of 0.08% (CI 0.02–0.15). International values are 0.0125% for sarcoidosis, 0.0035% for GBS, and 0.0051% for myositis. Thus, these diseases seem to be more frequent in our cohort, suggesting a higher frequency in HIV population.
We found 0.04% of MG in our study (CI 0–0.1%) which is not significantly different from international prevalence, estimated at 0.0051%.
Regarding Graves’ disease, we found only 2 cases (0.04%) (CI 0–0.1%), which is less than international values (1.151%).
For ITP, we found fifteen cases (0.29%) (CI, 0.15–0.44), which is more than international values (0.025%), but less than described in other case series and cohort studies.[11–15]
4.2 From serological markers of autoimmunity to clinical manifestations
The chronic infection by HIV results in production of cytokines, including interleukin 1 and interleukin 6, which leads to activation of the CD4+ population and polyclonal B cell stimulation (in addition, production of interferon-γ will further activate the immune system). Such a mechanism may contribute to the immunopathogenesis of HIV and many other abnormalities.[29,30] The immune system is thus maintained in an activated state which maximizes viral expression and further induces CD4 receptors thereby increasing the number of cells which are susceptible to HIV infection.[31,32] Some authors suggested that clinical manifestations are the result of loss of regulatory CD8 T cells and the production of autoantibodies. An infectious trigger for immune activation is one of the discussed mechanisms in autoimmunity and would derive from molecular mimicry.[34,35] This emerging concept of molecular mimicry was suggested as a way for retroviruses to escape the innate immune surveillance. As a result, autoimmune diseases may only occur when there is no immunosuppression: the clinical latency with high viral load and still high CD4 count; and the immune restoration with still high CD4 count and low viral load. In between those 2 stages, there would be more immune complex or vasculitis and spondyloarthritis.
4.3 HIV-associated immune thrombocytopenic purpura
Thrombocytopenia is commonly observed among HIV-infected patients (5–30%) and may be the first manifestation of HIV infection. HIV-associated ITP is more prevalent in advanced HIV infection, meaning clinical acquired immunodeficiency syndrome (AIDS) or a CD4-lymphocyte count <200/mm3, with high viral load. We observed a predominance of ITP in men, which is consistent with the literature (25 men, 5 women in Ambler study, 34 men, 21 women in Nascimento study). Even if platelet count can be very low (<10 G/L), major bleeding is rare and only a few cases of severe bleeding, like intracranial hemorrhage, have been documented.
There are 2 mechanisms to explain HIV-related ITP. First, there is an immune-mediated peripheral platelet destruction, like in classic ITP, with anti-GpIIIa antibodies and the action of immune complexes.[37,38] This is more frequent early in HIV infection. The second mechanism is a defect of platelet production because of the infection of the megakaryocytes of the bone marrow, which usually occurs at an advanced stage of AIDS. Of course, thrombocytopenia can also be secondary to drugs, opportunistic diseases, hypersplenism, lymphoma, or other infections. These causes of secondary thrombocytopenia were excluded in our study.
HIV-associated ITP is generally responsive to therapeutic interventions used in classical ITP: steroids, intravenous immunoglobulins, splenectomy, associated with antiretroviral therapy, when it occurs early in HIV infection. These classical ITP drugs seem to be less effective in patients with advanced disease because of central infection of the megakaryocyte. Thrombopoietic agents might be interesting in this case, improving T-regulatory cells function and restoring immune tolerance. Only 2 cases are described in HIV-infected patients and were effective.[41,42]
4.4 Sarcoidosis and HIV
Sarcoidosis is an immune-mediated disease of unknown origin, in which the CD4 Th1 type immune response is thought to play an important role, with CD4 T lymphocytes accumulation in active granulomas. This pathogenesis might explain why sarcoidosis was rarely reported in AIDS patients. As in 3 of our 4 patients, cases of sarcoidosis are usually described as a form of delayed IRIS in patients receiving HAART.[43–45] Interestingly, as for 2 of our patients (1 HCV coinfected and 1 HBV coinfected) sarcoidosis has been reported to occur after interferon-alpha therapy in both HIV-positive and HIV-negative patients.[6,46] Therefore, it appears that immune reconstitution after T cell depletion resulting from a number of causes, including HIV infection, is associated with an increased susceptibility to immune dysregulation. This dysregulation induces the Th1 immune responses against unknown antigens, producing interferon-gamma, interleukin 2, tumor necrosis factor, that underlies the granulomatous inflammation of sarcoidosis.[47,48] The susceptibility to dysregulated Th1 immune responses is presumably increased further by the use of interferon-alpha therapy, which enhances Th1 responses. In this context, it is important to differentiate immune reconstitution-associated sarcoidosis from mycobacterial and fungal immune restoration diseases. Clinical and radiological characteristics, laboratory values for bronchoalveolar fluid samples, and course of sarcoidosis are similar to that observed in HIV-seronegative patients.[6,49] One of our patients presented a disseminated form with neurologic involvement which required oral steroids.
4.5 HIV-associated myositis
HIV-associated PM was first described in 1986, and several reports within the last years confirm this association.[51–54] Dermatomyositis is also seen in HIV infection, but is rarer.[55–57] The clinical course (progressive, proximal, and symmetric weakness), laboratory (elevated serum creatine phosphokinase which can be absent), electromyography and myopathic muscle biopsy findings are similar to the idiopathic form.[52,53,58,59] Demography in previous studies is discordant, since in 1 American series, all except 1 were men, while in 1 South African series all were women.[53,58]
Physiopathology of PM during HIV infection remains poorly understood. It can occur in all stages of HIV infection, from asymptomatic individuals to those with advanced AIDS. There is no correlation with the degree of immunodeficiency.[52,53,58] The loss of CD4 T lymphocytes during the course of HIV infection may contribute to the immune dysregulation and the generation of autoreactive CD8 T lymphocytes, which might increase CD8 T lymphocyte mediated AD such as PM.[1,52]
Corticosteroids are the most common treatment used in HIV-associated myositis, while second-line agents include immunoglobulins, methotrexate, and azathioprine.[52,53] Some cases can improve without any immunosuppressive therapy or, as one of our patient, under antiretroviral therapy alone. Some patients can keep significant weakness for many years despite these treatments, as 2 of our patients at last follow-up.
One of our treatment refractory patient was a woman with anti-JO1 antibodies; this case is, to our knowledge, the first description of this type of inflammatory myopathy associated in an HIV patient. She presented classical clinical manifestations of myositis (proximal weakness, myalgia), associated with mechanic's hands, dactylitis, and interstitial lung disease. She has been treated with steroids, immunoglobulins, azathioprine, and methotrexate without any effectiveness and now receives rituximab.
It is important to differentiate HIV-associated myositis from toxic myopathy (zidovudine, stavudine) where symptoms recede at the end of antiretroviral treatment and muscle biopsy reveals ragged red fibers.
4.6 Neurologic disorders associated with HIV infection
Neurologic complications are present at all stages of HIV infection. They include HIV neurological diseases, treatment-related neurological diseases, and neoplasic or opportunistic neurological disorders. As in our study, GBS usually occurs either as an acute neurologic manifestation in a primary HIV infection, at the seroconversion time, or within the first 3 to 6 months after the initiation of antiretroviral therapy.[63,64] It can also occur later during HIV infection but generally in the presence of high CD4+ T lymphocytes counts.
The mechanisms proposed include a direct action of HIV-1 on the nerves, by neurotropic strains, or autoimmune mechanisms, with the formation of antibodies against myelin secondary to the immune dysregulation by HIV infection.
The outcome of GBS in HIV-infected subjects is often favorable with complete remission or mild aftereffects (as in our series), although fast clinical deterioration, as respiratory failure, or deaths have been reported. One study showed similar outcomes in HIV-positive and HIV-negative patients with GBS.
Among treatments, plasmapheresis or immunoglobulins can be used, but the later are preferred because of their easier use.[65,67]
MG is rare during HIV infection. There are a few case reports in the literature but a causal relationship has not been shown.[52,69] Pyridostigmine is the most common treatment but use of steroids, azathioprine, cyclosporine, immunoglobulins, and rituximab has been reported.[70–73]
4.7 Autoimmune thyroid diseases and HIV
Autoimmune thyroid diseases are the most common autoimmune disease in the world. More and more authors have shown the association between HIV and autoimmune thyroid disorders. Small studies report a prevalence rate of Hashimoto thyroiditis to be up to 2.6% in HIV positive patients. Some authors described Graves’ disease as a manifestation of delayed IRIS and suggested that CD4 T lymphocytes could play a role in its occurrence.[75,76] Other authors found no association between HIV infection and thyroid dysfunction.[77–79]
4.8 Rheumatoid arthritis associated with HIV infection
We found 1 patient with RA in our case series. RA associated with HIV infection is quite rare.[80–82] Stein found only 1 case of RA with erosive arthritis in his 58 HIV infected-patient cohort with arthritis. In Cunha review of the literature, 9 of 198 HIV patients with arthritis presented with a rheumatoid pattern. Clinical presentation, biologic features, and radiologic erosions are similar to that observed in HIV-negative patients. RA usually occurs when immunity is reconstituted by HAART. The role of CD4 T cells in RA pathogenesis is debated but some cases of RA improvement after HIV infection, mediated by a decrease in CD4 T cells, have been described.
However, rheumatoid factor and anticyclic citrullinated peptide antibodies can be detected in HIV-infected patients, without any rheumatic complaint.
4.9 Autoimmune hepatitis and HIV
Autoimmune hepatitis during HIV infection is extremely rare and we found, in addition to our case, only 14 cases reported in the literature.[16,85–89] It has been reported during immune reconstitution, or during a good immunovirological control with HAART. A favorable impact of HAART is suggested by some authors. Standard immunosuppressive therapy, even in HIV positive patients, is described as the optimal treatment by other authors.
4.10 Autoimmune hemolytic anemia and HIV
AHA is rare in HIV-infected people, and the hemoglobin level is lower in patients at CDC stage B or C. AHA usually occurs at an advanced stage of HIV disease. The response to steroids is often excellent, as for our patient. Direct antiglobulin test can give false-positive results in HIV-infected patients. Some cases of AHA during HIV infection are described, during angiotropic large cell lymphoma, Burkitt lymphoma or diffuse large B-cell lymphoma, and during Castleman disease.[92–95]
4.11 Systemic lupus erythematosus and HIV
SLE during HIV infection is rare. Fifty-five cases have been identified by Carugati in the literature between 1981 and 2012. SLE diagnosis during HIV infection is difficult, because there are many clinical and laboratory similarities between the 2 diseases (oral ulcerations, sicca syndrome, arthritis, fever, neuropathies, cytopenias, hypergammaglobulinemia). Further, antinuclear antibodies and antiphospholipid antibodies can be positive during HIV infection. Because CD4 T lymphocytes play an important part in SLE pathogenesis, SLE generally improves during the course of untreated HIV infection. Our case had an initial glomerulonephritis, which had been treated by cyclophosphamide. After HIV infection, he only presented cutaneous and articular manifestations, controlled by methotrexate and steroids.
4.12 Vasculitis and HIV
We did not identify any patient with vasculitis associated with HIV infection in our study, although these disorders have been reported at all stages of HIV infection. Incidence is estimated less than 1%. Vasculitis mostly affects small, or medium-sized vessels and is not related to antineutrophil cytoplasm antibodies (ANCA). Various pathogenic mechanisms have been proposed in this setting, including cell-mediated inflammation, immune complex-mediated inflammation and autoantibody-mediated inflammation. Relapse is unusual. ANCA positivity by indirect immunofluorescence is reported in 13% to 42% of HIV patients, but antigen-specific ELISA is usually negative. Several cases of Behcet disease during HIV infection have been described.[103–106] Diagnosis is challenging, because the 2 diseases share many clinical features: oral and genital ulcers, arthritis, uveitis, and skin lesions.[104,105] The course of the disease seems to be improved by HAART.[105,106]
4.13 Use of immunosuppressant treatment during HIV infection
Immunosuppressant treatments used in our case series are classical, according to reference treatments in non-HIV population, and to literature in HIV-infected subjects, as we have already detailed for each AD.
For a few patients, HAART alone is enough; autoimmune manifestations are directly HIV-related and improve with restauration of immunity, as during GBS at time of seroconversion or for ITP, at any stage of the infection.[38,39] The most frequent and the most effective seem to be immunosuppressant treatments, in association with HAART. These treatments are well tolerated in our case series, with a few of complications (only 1 severe osteoporosis and 5 cytopenias in our study and no severe side effects in the literature).
Our work has some limits and potential bias. First, it is a retrospective, monocentric study, led from informatical coding in a hospital information system. Because the diagnoses and data have all been checked against patient medical record with a standardized form, we believe our specificity for case selection is good. On the other hand, our screening methodology may have underestimated the prevalence of ADs due to unknown sensitivity of our extraction algorithms and potential loss of follow-up. As person-time of observation was not available, we could not estimate the incidence rates. Then, we did not compare AD cases with non-AD cases in our HIV-infected patients database.
Furthermore, we compared a cross sectional estimate of prevalence in our study with international studies which are heterogeneous: American data for MG, myositis and Graves’ disease, European data for GBS and ITP and global data for sarcoidosis. Those estimations would deserve more accurate measurement based on multicentric incidence studies. Finally the good tolerance of immunosuppressant drug in our series should be confirmed with a large number of patients.
AD during HIV infection is a rare event. Sarcoidosis, ITP, IM, and neurologic manifestations seem to be more frequent in our cohort than in the general population. Except ITP which is more prevalent in advanced HIV infection, they occur most often in a context of effective HAART with good immunological response or during IRIS. GBS often occur at the time of HIV infection diagnosis. Their clinical manifestations are quite similar to the general population. HAART allows immune modulations, with immune restoration and development of autoimmune manifestations. Immunosuppressant drugs in this context seem to be effective, often well tolerated and not associated with new opportunistic infection.
The authors thank Soifya Daoud, Olivier Loria, and Anthony Heredia for their technical help for this study.
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Keywords:Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
acquired immunodeficiency syndrome (AIDS); autoimmune disease; highly active antiretroviral therapy (HAART); human immunodeficiency virus (HIV); immune restoration inflammatory syndrome (IRIS); immune thrombocytopenic purpura (ITP); immunosuppressant drugs